1. Field of the Invention
This invention relates to new antibacterial agents which interfere in bacterial cell wall synthesis by inhibiting the enzyme D-Ala-D-Ala ligase. Compounds of this invention also inhibit renal dehydropeptidase (DHP) and, therefore, potentiate the antibiotic activity of carbapenem antibiotics.
2. Brief Description of the Art
Many antibacterial agents owe their selective toxicity to the fact that their targets are structures which are only present in the sensitive bacterium. One of these structures in peptidoglycan a cell wall polymer which plays a vital role in protecting bacteria from lysis. A number of agents, e.g., .beta.-lactams, bacitracin, and flavomycin, interfere with the assembly of this polymer by inhibiting enzymatic reactions involved in the final stages of assembly.
Peptidoglycan biosynthesis involves a precursor, UDP-MurNAc-Ala-D-Glu-Lys-D-Ala-D-Alanine that is biosynthesized in a multienzyme pathway which terminates in the addition of D-Alanine-D-Alanine to the UDP-MurNAc-tripeptide. The formation of D-Alanyl-D-Alanine is catalyzed by D-Alanyl-D-Alanine ligase (synthetase). It is known that inhibition of D-Alanyl-D-Alanyl ligase will terminate peptidoglycan biosynthesis resulting in vivo in bacterial cell lysis. Such inhibitors can serve as antibacterials. For example, D-Cycloserine, a D-Alanine mimic, is a reversible inhibitor of the ligase at both the donor and acceptor sites and is the most potent ligase inhibitor described heretofore, and is a potent antibacterial. (F. C. Neuhaus et al., Biochemistry 3, 471-480 (1964)).
Dipeptide analogs of D-Alanyl-D-Alanine are also known to be inhibitors of ligase. (F. C. Neuhaus et al., Biochemistry 8, 5119-5124 (1965), and F. C. Neuhaus and W. P. Hammes, Pharmac. Ther. 14, 265-319 (1981)).
Renal dehydropeptidase (E.C. 3.4.13.11) is a mammalian enzyme which metabolizes carbapenem antibiotics such as thienamycin and imipenem. Inhibition of this enzyme enhances the urinary recovery of these antibiotics and reduces their renal toxicity. EPO Publication No. 0091594 to Sanraku-Ocean Co., Ltd. described aminocarboxylic acid derivatives possessing dipeptidase inhibiting activity. This subject and the development of cilastatin as a renal dehydropeptidase inhibitor for use in combination with imipenem have also been reviewed be F. M. Kahan et al., J. Antimicrobial Chemotherapy, 12, Suppl. D, 1-35 (1983).
U.S. Pat. No. 4,374,131 to Petrillo (assigned to E. R. Squibb & Sons, Inc.) discloses amino and substituted amino phosphinyl-alkanoyl compounds which are useful hypertensive agents due to their angiotensin-converting-enzyme (ACE) inhibition activity.
E. D. Thorsett et al., (Merck & Co., Inc.) Proc. Natl. Acad. Sci. USA Vol. 79, pp, 2176-2180 (April 1982) discloses phosphorus containing inhibitors of angiotensin-converting enzyme.
With this background, the search for newer and more effective antibacterial agents which are ligase inhibitors, is a continuing one.